Cellular Uptake of Tau Aggregates Triggers Disulfide Bond Formation in Four-Repeat Tau Monomers.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 101525337 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1948-7193 (Electronic) Linking ISSN: 19487193 NLM ISO Abbreviation: ACS Chem Neurosci Subsets: MEDLINE

Original Publication: Washington, D.C. : American Chemical Society

tau Proteins*/metabolism ; Disulfides*/metabolism ; Disulfides*/chemistry; Humans ; HEK293 Cells ; Protein Aggregates/physiology ; Oxidation-Reduction

Oxidative stress is an important driver of aging and has been linked to numerous neurodegenerative disorders, including Alzheimer's disease. A key pathological hallmark of Alzheimer's are filamentous inclusions made of the microtubule associated protein Tau. Based on alternative splicing, Tau protein can feature either three or four microtubule binding repeats. Distinctively, three-repeat Tau contains a single cysteine; four-repeat Tau contains two. Although there is evidence that the cysteines in pathological Tau filaments exist in the reduced form, very little is known about the alternative disulfide-bonded state. It is unclear whether it can exist nontransiently in the reducing environment of the cytosol. Such knowledge, however, is important as different redox states of Tau could modulate aggregation. To address this question, we transfected HEK293 cells expressing the P301S variant of four-repeat Tau with fibril seeds composed of compact, disulfide-bonded Tau monomers. In vitro, these fibrils are observed to recruit only compact Tau, but not Tau in which the cysteines are reduced or replaced by alanines or serines. In line with this characteristic, the fibrils dissociate when treated with a reducing agent. When offered to HEK293 cells, variant Tau protein is recruited to the seeds forming intracellular fibrils with the same seeding properties as the in vitro counterparts. Markedly, the proteins in these fibrils have a compact, disulfide-bonded configuration and dissociate upon reduction. These findings reveal that uptake of exogeneous fibril seeds triggers oxidation of Tau monomers, modulating intracellular aggregation.

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RF1 AG061566 United States AG NIA NIH HHS

Keywords: Alzheimer’s disease; Tau protein; aggregation; amyloid; conformation; disulfide; fibril; redox switch; seeding barrier; thiol

0 (tau Proteins)
0 (Disulfides)
0 (Protein Aggregates)
0 (MAPT protein, human)

Date Created: 20241223 Date Completed: 20250115 Latest Revision: 20250120

20250120

PMC11740991

10.1021/acschemneuro.4c00607

39714208